(carboxylalkylenephenyl)phenyloxamides, method for the production thereof and use of same as a medicament

ABSTRACT

The invention relates to (carboxylalkylenephenyl)phenyloxamides and their physiologically tolerated salts, and their use as a medicament.

The invention relates to (carboxylalkylenephenyl)phenyloxamides andtheir physiologically tolerated salts.

Compounds of similar structure have been described in the prior art (seeUS2005/0124667), as well as the use thereof as antithrombotics.

The invention was based on the object of providing compounds whichdisplay a therapeutically useful effect. The object was in particular tofind novel compounds suitable for the treatment of hyperglycemia anddiabetes.

The invention therefore relates to compounds of the formula I

in which the meanings are

-   R3 independently of one another H, F, Cl, Br, CN, CF₃, OH, OCF₃,    OCHF₂, SCH₃, SCF₃, phenyl, Ophenyl, COOH, COO—(C₁-C₆)-alkyl,    CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl,    O—(C₁-C₆)-alkyl, OBn, SO₂—(C₁-C₄)-alkyl, SO₃H, SO₂NR9R10, NR9R10 or    SO₂—N-piperidinyl, where alkyl and phenyl may be substituted one or    more times by R12;-   R1, R5 independently of one another H, F, Cl, Br, CN, CF₃, SCH₃,    SCF₃, phenyl, Ophenyl, COOH, COO—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl,    (C₁-C₆)-alkyl, SO₂—(C₁-C₄)-alkyl, SO₃H, SO₂NR9R10, NR9R10 or    SO₂—N-piperidinyl, where alkyl and phenyl may be substituted one or    more times by R12;-   R2, R4 independently of one another H, F, Cl, Br, CN, CF₃, OCF₃,    OCHF₂, SCH₃, SCF₃, phenyl, Ophenyl, COOH, COO—(C₁-C₆)-alkyl,    CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, OBn,    SO₂—(C₁-C₄)-alkyl, SO₃H, SO₂NR9R10, NR9R10 or SO₂—N-piperidinyl,    where alkyl and phenyl may be substituted one or more times by R12;-   R7, R8 independently of one another H or (C₁-C₆)-alkyl;-   X (C₂-C₃)-alkylene, where alkylene may be substituted one or more    times by R11;-   m 0, 1, 2, 3 or 4;-   R6 OH, F, Cl, Br, CN, OCH₃, OCF₃, CH₃, CF₃, (C₁-C₆)-alkyl or    O—(C₁-C₆)-alkyl, where alkyl may be substituted one or more times by    OH, F, Cl, Br or CN;-   R9, R10 independently of one another H, (C₁-C₆)-alkyl or phenyl,    where alkyl may be substituted one or more times by F, Cl or Br, and    phenyl may be substituted one or more times by R6;-   R11 F, Cl, Br, CN, OH, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl or NR9R10;-   R12 F, Cl, Br, CN, OH, 0-(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, NR9R10, COOH, COO—(C₁-C₄)-alkyl,    SCH₃, SCF₃, SO₂—(C₁-C₄)-alkyl, SO₃H or SO₂NR9R10;    and the physiologically tolerated salts thereof.

Preference is given to compounds of the formula I in which one or moreradicals have the following meanings:

-   R3 independently of one another H, F, Cl, Br, CF₃, OCF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₈)-Cycloalkyl, phenyl,    Ophenyl, where alkyl and phenyl may be substituted one or more times    by R12;-   R1, R5 independently of one another H, F, Cl, Br, CF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, phenyl, Ophenyl, where alkyl and    phenyl may be substituted one or more times by R12;-   R2, R4 independently of one another H, F, Cl, Br, CF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl;-   R6 OH, F, Cl, Br, CN, OCH₃, OCF₃, CH₃, CF₃, (C₁-C₆)-alkyl or    O—(C₁-C₆)-alkyl, where alkyl may be substituted one or more times by    OH, F, Cl, Br or CN;-   R7, R8H;-   X (C₂-C₃)-alkylene, where alkylene may be substituted one or more    times by R11;-   m 0;-   R9, R10 independently of one another H, (C₁-C₆)-alkyl or phenyl,    where alkyl may be substituted one or more times by F, Cl or Br, and    phenyl may be substituted one or more times by R6;-   R11 F, Cl, Br, CN, OH, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl or NR9R10;-   R12 F, Cl, Br, CN, OH, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, NR9R10, COOH, COO—(C₁-C₄)-alkyl;    and the physiologically tolerated salts thereof.

Particular preference is given to compounds of the formula I in whichone or more radicals have the following meanings:

-   R3 independently of one another H, F, Cl, Br, CF₃, OCF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, phenyl;-   R1, R5 independently of one another H, F, Cl, Br, CF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, phenyl;-   R2, R4 independently of one another H, F, Cl, Br, CF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl;-   R7, R8 H;-   X (C₂-C₃)-alkylene, where alkylene may be substituted one or more    times by R11;-   m 0;-   R11 (C₂-C₆)-alkynyl;    and the physiologically tolerated salts thereof.

Particular preference is further given to compounds of the formula I inwhich one or more radicals have the following meanings:

-   R3 independently of one another H, F, Cl, Br, CF₃, OCF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, phenyl;-   R1, R5 independently of one another H, F, Cl, Br, CF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, phenyl;-   R2, R4 independently of one another H, F, Cl, Br, CF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl;-   R7, R8 H;-   X (C₂-C₃)-alkylene, where X is linked in position 4 to the ring;-   m 0;    and the physiologically tolerated salts thereof.

In a further embodiment, preference is given to compounds of the formulaI in which one or more radicals have the following meanings:

-   R3 independently of one another H, F, Cl, Br, CN, CF₃, OH, OCF₃,    OCHF₂, SCH₃, SCF₃, phenyl, Ophenyl, COOH, COO—(C₁-C₆)-alkyl,    CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, OBn,    SO₂—(C₁-C₄)-alkyl, SO₃H, SO₂NR9R10, NR9R10 or SO₂—N-piperidinyl,    where alkyl and phenyl may be substituted one or more times by R12;-   R1, R5 independently of one another H, F, Cl, Br, CN, CF₃, SCH₃,    SCF₃, phenyl, Ophenyl, COOH, COO—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl,    (C₁-C₆)-alkyl, SO₂—(C₁-C₄)-alkyl, SO₃H, SO₂NR9R10, NR9R10 or    SO₂—N-piperidinyl, where alkyl and phenyl may be substituted one or    more times by R12;-   R2, R4 independently of one another H, F, Cl, Br, CN, CF₃, OCF₃,    OCHF₂, SCH₃, SCF₃, phenyl, Ophenyl, COOH, COO—(C₁-C₆)-alkyl,    CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, OBn,    SO₂—(C₁-C₄)-alkyl, SO₃H, SO₂NR9R10, NR9R10 or SO₂—N-piperidinyl,    where alkyl and phenyl may be substituted one or more times by R12;-   R7, R8 independently of one another H or (C₁-C₆)-alkyl;-   X (C₂-C₃)-alkylene, where alkylene may be substituted one or more    times by R11;-   m 0, 1, 2, 3 or 4;-   R6 OH, F, Cl, Br, CN, OCH₃, OCF₃, CH₃, CF₃, (C₁-C₆)-alkyl or    O—(C₁-C₆)-alkyl, where alkyl may be substituted one or more times by    OH, F, Cl, Br or CN;-   R9, R10 independently of one another H, (C₁-C₆)-alkyl or phenyl,    where alkyl may be substituted one or more times by F, Cl or Br, and    phenyl may be substituted one or more times by R6;-   R11 F, Cl, Br, CN, OH, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl or NR9R10;-   R12 F, Cl, Br, CN, OH, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, NR9R10, COOH, COO—(C₁-C₄)-alkyl,    SCH₃, SCF₃, SO₂—(C₁-C₄)-alkyl, SO₃H or SO₂NR9R10;    and the physiologically tolerated salts thereof.

In a further embodiment, preference is given to compounds of the formulaI in which one or more radicals have the following meanings:

-   R3 independently of one another H, F, Cl, Br, CF₃, OCF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, phenyl, Ophenyl, where alkyl and    phenyl may be substituted one or more times by R12;-   R1, R5 independently of one another H, F, Cl, Br, CF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, phenyl, Ophenyl, where alkyl and    phenyl may be substituted one or more times by R12;-   R2, R4 independently of one another H, F, Cl, Br, CF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl;-   R6 OH, F, Cl, Br, CN, OCH₃, OCF₃, CH₃, CF₃, (C₁-C₆)-alkyl or    O—(C₁-C₆)-alkyl, where alkyl may be substituted one or more times by    OH, F, Cl, Br or CN;-   R7, R8 H;-   X (C₂-C₃)-alkylene, where alkylene may be substituted one or more    times by R11;-   m 0;-   R9, R10 independently of one another H, (C₁-C₆)-alkyl or phenyl,    where alkyl may be substituted one or more times by F, Cl or Br, and    phenyl may be substituted one or more times by R6;-   R11 F, Cl, Br, CN, OH, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl or NR9R10;-   R12 F, Cl, Br, CN, OH, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,    (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, NR9R10, COOH, COO—(C₁-C₄)-alkyl;    and the physiologically tolerated salts thereof.

In a further embodiment, preference is given to compounds of the formulaI in which one or more radicals have the following meanings:

-   R3 independently of one another H, F, Cl, Br, CF₃, OCF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, phenyl;-   R1, R5 independently of one another H, F, Cl, Br, CF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, phenyl;-   R2, R4 independently of one another H, F, Cl, Br, CF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl;-   R7, R8 H;-   X (C₂-C₃)-alkylene;-   m 0;    and the physiologically tolerated salts thereof.

In a further embodiment, preference is given to compounds of the formulaI in which one or more radicals have the following meanings:

-   R3 independently of one another H, F, Cl, Br, CF₃, OCF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl;-   R1, R5 independently of one another H, F, Cl, Br, CF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, phenyl;-   R2, R4 independently of one another H, F, Cl, Br, CF₃, COOH,    COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl;-   R7, R8 H;-   X (C₂-C₃)-alkylene, where X is linked in position 4 to the ring;-   m 0;    and the physiologically tolerated salts thereof.

Compounds of the formula I preferred in one embodiment are those inwhich X is —(CH₂)_(2—).

Compounds of the formula I preferred in one embodiment are those inwhich X is —(CH₂)₃—.

Compounds of the formula I preferred in one embodiment are those inwhich the group —X—COOH is linked in position 3 to the ring.

Compounds of the formula I preferred in one embodiment are those inwhich the group —X—COOH is linked in position 4 to the ring.

If radicals or substituents can occur more than once in the compounds ofthe formulae I, they may all have the stated meaning independently ofone another and be identical or different.

The alkyl, alkenyl, alkynyl and alkylene radicals in the radicals X, R1,R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 may be eitherstraight-chain or branched.

The invention relates to compounds of the formula I in the form of theirsalts, racemates, racemic mixtures and pure enantiomers, and theirdiastereomers and mixtures thereof.

The invention further relates both to mixtures of stereoisomers of theformula I and to the pure stereoisomers of the formula I, and tomixtures of diastereomers of the formula I and to the purediastereomers. The mixtures are separated for example by chromatographicmeans.

The present invention includes all possible tautomeric forms of thecompounds of the formula I.

Pharmaceutically acceptable salts are, because their solubility in wateris greater than that of the initial or basic compounds, particularlysuitable for medical applications. These salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the invention aresalts of inorganic acids such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acid, and of organicacids such as, for example, acetic acid, benzenesulfonic, benzoic,citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic,lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonicand tartaric acid. Suitable pharmaceutically acceptable basic salts areammonium salts, alkali metal salts (such as sodium and potassium salts),alkaline earth metal salts (such as magnesium and calcium salts),trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine,lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion such as, for example,trifluoroacetate likewise belong within the framework of the inventionas useful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for use in nontherapeutic, forexample in vitro, applications.

The compounds of the invention may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds of the invention belong within theframework of the invention and are a further aspect of the invention.

All references to “compound(s) of formula I” hereinafter refer tocompound(s) of the formula I as described above, and their salts andsolvates as described herein.

An alkyl radical means a straight-chain or branched hydrocarbon chainsuch as, for example, methyl, ethyl, isopropyl, tert-butyl, hexyl. Thealkyl radicals may be substituted one or more times as described above.

The invention also includes solvates, hydrates and alcohol adducts ofthe compounds of the formula I.

The compound(s) of the formula I can also be administered in combinationwith further active ingredients.

The amount of a compound of formula I necessary to achieve the desiredbiological effect depends on a number of factors, for example thespecific compound chosen, the intended use, the mode of administrationand the clinical condition of the patient. The daily dose is generallyin the range from 0.3 mg to 100 mg (typically from 3 mg and 50 mg) perday and per kilogram of body weight, for example 3-10 mg/kg/day. Anintravenous dose may be for example in the range from 0.3 mg to 1.0mg/kg, which can suitably be administered as infusion of from 10 ng to100 ng per kilogram per minute. Suitable infusion solutions for thispurpose may comprise for example from 0.1 ng to 100 mg, typically from 1ng to 100 mg, per milliliter. Single doses may comprise for example from1 mg to 10 g of the active ingredient. Thus, ampoules for injections maycomprise for example from 1 mg to 100 mg, and single-dose formulationswhich can be administered orally, such as, for example, tablets orcapsules, may comprise for example from 1.0 to 1000 mg, typically from10 to 600 mg. For the therapy of the abovementioned conditions, thecompounds of formula I may be used as the compound itself, but they arepreferably in the form of a pharmaceutical composition with anacceptable carrier. The carrier must, of course, be acceptable in thesense that it is compatible with the other ingredients of thecomposition and is not harmful for the patient's health. The carrier maybe a solid or a liquid or both and is preferably formulated with thecompound as a single dose, for example as a tablet, which may containfrom 0.05% to 95% by weight of the active ingredient. Otherpharmaceutically active substances may likewise be present, includingother compounds of formula I. The pharmaceutical compositions of theinvention can be produced by one of the known pharmaceutical methods,which essentially consist of mixing the ingredients withpharmacologically acceptable carriers and/or excipients.

Pharmaceutical compositions of the invention are those suitable fororal, rectal, topical, peroral (for example sublingual) and parenteral(for example subcutaneous, intramuscular, intradermal or intravenous)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the nature of the compound of formula Iused in each case. Coated formulations and coated slow-releaseformulations also belong within the framework of the invention.Preference is given to acid- and gastric juice-resistant formulations.Suitable coatings resistant to gastric juice comprise cellulose acetatephthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosephthalate and anionic polymers of methacrylic acid and methylmethacrylate.

Suitable pharmaceutical compounds for oral administration may be in theform of separate units such as, for example, capsules, cachets, suckabletablets or tablets, each of which contains a defined amount of at leastone compound of formula I; as powders or granules; as solution orsuspension in an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. These compositions may, as already mentioned, beprepared by any suitable pharmaceutical method which includes a step inwhich the active ingredient and the carrier (which may consist of one ormore additional ingredients) are brought into contact. The compositionsare generally produced by uniform and homogeneous mixing of the activeingredient with a liquid and/or finely divided solid carrier, afterwhich the product is shaped if necessary. Thus, for example, a tabletcan be produced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one (ormore) surface-active/dispersing agent(s) in a suitable machine. Moldedtablets can be produced by molding the compound, which is in powder formand is moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration comprise suckable tablets which contain a compound offormula I with a flavoring, normally sucrose and gum arabic ortragacanth, and pastilles which comprise the compound in an inert basesuch as gelatin and glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administrationinclude preferably sterile aqueous preparations of a compound of formulaI, which are preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration may also take place by subcutaneous,intramuscular or intradermal injection. These preparations canpreferably be produced by mixing the compound with water and making theresulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally comprise from 0.1 to 5% byweight of the active compound.

Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of formula I with one or more conventionalsolid carriers, for example cocoa butter, and shaping the resultingmixture.

Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aerosolor oil. Carriers which can be used are petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.The active ingredient is generally present in a concentration of from0.1 to 15% by weight of the composition, for example from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal uses can be in the form of single patches whichare suitable for long-term close contact with the patient's epidermis.Such patches suitably contain the active ingredient in an aqueoussolution which is buffered where appropriate, dissolved and/or dispersedin an adhesive or dispersed in a polymer. A suitable active ingredientconcentration is about 1% to 35%, preferably about 3% to 15%. Aparticular possibility is for the active ingredient to be released byelectrotransport or iontophoresis as described, for example, inPharmaceutical Research, 2(6): 318 (1986).

Further active ingredients suitable for combination products are:

All antidiabetics which are mentioned in the Rote Liste 2007, chapter12; all weight-reducing agents/appetite suppressants which are mentionedin the Rote Liste 2007, chapter 1; all lipid-lowering agents which arementioned in the Rote Liste 2007, chapter 58. They can be combined withthe compounds of the invention of the formula I in particular for asynergistic improvement in the effect. Administration of the activeingredient combination can take place either by separate administrationof the active ingredients to the patient or in the form of combinationproducts in which a plurality of active ingredients are present in onepharmaceutical preparation. Most of the active ingredients mentionedhereinafter are disclosed in the USP Dictionary of USAN andInternational Drug Names, US Pharmacopeia, Rockville 2001.

Antidiabetics include insulin and insulin derivatives such as, forexample, LANTUS® (see www.lantus.com) or HMR 1964 or LEVEMIR® (insulindetemir) or those described in WO2005005477 (Novo Nordisk), fast-actinginsulins (see U.S. Pat. No. 6,221,633), inhalable insulins such as, forexample, EXUBERA® or oral insulins such as, for example, IN-105 (NOBEX)or ORAL-LYN™ (Generex Biotechnology), GLP-1-derivatives and GLP-1agonists such as, for example, exenatide, liraglutide or those whichhave been disclosed in WO98/08871 or WO2005027978, WO2006037811,WO2006037810 of Novo Nordisk A/S, in WO01/04156 of Zealand or inWO00/34331 of Beaufour-Ipsen, pramlintide acetate (Symlin; AmylinPharmaceuticals), BIM-51077, PC-DAC:Exendin-4 (an Exendin-4 analog whichis covalently bonded to recombinant human albumin), agonists like thosedescribed for example in D. Chen et al., Proc. Natl. Acad. Sci. USA 104(2007) 943, those described in WO2006124529, and orally effectivehypoglycemic active ingredients.

Antidiabetics also include agonists of the glucose-dependentinsulinotropic polypeptide (GIP) receptor like those described forexample in WO2006121860.

The orally effective hypoglycemic active ingredients include preferably

sulfonylureas,biguanidines,meglitinides,oxadiazolidinediones,thiazolidinediones,glucosidase inhibitors,inhibitors of glycogen phosphorylase,glucagon antagonists,glucokinase activators,inhibitors of fructose 1,6-bisphosphatasemodulators of glucose transporter 4 (GLUT4),inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT),GLP-1 agonists,potassium channel openers such as, for example, Pinacidil, Cromakalim,Diazoxide or those described in R. D. Carr et al., Diabetes 52, 2003,2513, 2518, in J. B. Hansen et al., Current Medicinal Chemistry 11,2004, 1595-1615, in T. M. Tagmose et al., J. Med. Chem. 47, 2004,3202-3211 or in M. J. Coghlan et al., J. Med. Chem. 44, 2001, 1627-1653,or those which have been disclosed in WO 97/26265 and WO 99/03861 ofNovo Nordisk A/S,inhibitors of dipeptidylpeptidase IV (DPP-IV),insulin sensitizers,inhibitors of liver enzymes involved in stimulating gluconeogenesisand/or glycogenolysis,modulators of glucose uptake, of glucose transport and of glucosereabsorption,inhibitors of 11β-HSD1,inhibitors of protein tyrosine phosphatase 1B (PTP1B),modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1,SGLT2),compounds which alter lipid metabolism such as antihyperlipidemic activeingredients and antilipidemic active ingredients,compounds which reduce food intake,compounds which increase thermogenesis,PPAR and RXR modulators (retinoid X receptor) and active ingredientswhich act on the ATP-dependent potassium channel of the beta cells.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an HMGCoA reductase inhibitor(3-hydroxy-3-methylglutaryl coenzyme A) such as simvastatin,fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin,rosuvastatin or L-659699

In one embodiment of the invention, the compound of the formula I isadministered in combination with a cholesterol absorption inhibitor suchas, for example, ezetimibe, tiqueside, pamaqueside, FM-VP4(sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech,WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497,WO2005021495) or with compounds as described in WO2002066464,WO2005000353 (Kotobuki Pharmaceutical Co. Ltd.) or WO2005044256 orWO2005062824 (Merck & Co.) or WO2005061451 and WO2005061452 (AstraZenecaAB), and WO2006017257 (Phenomix) or WO2005033100 (Lipideon BiotechnologyAG), or in WO2004097655, WO2004000805, WO2004000804, WO2004000803,WO2002050068, WO2002050060, WO2005047248, WO2006086562, WO2006102674,WO2006116499, WO2006121861, WO2006122186, WO2006122216, WO2006127893,WO2006137794, WO2006137796, WO2006137782, WO2006137793, WO2006137797,WO2006137795, WO2006137792, WO2006138163.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Vytorin™, a fixed combination ofezetimibe with simvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a fixed combination of ezetimibe withatorvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a fixed combination of ezetimibe withfenofibrate.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a fixed combination of fenofibratewith rosuvastatin.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with Synordia (R), a fixed combination offenofibrate with metformin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with ISIS-301012, an antisenseoligonucleotide able to regulate the apolipoprotein B gene.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR (peroxisome proliferatoractivated receptor) gamma agonist such as, for example, rosiglitazone,pioglitazone, JTT-501, G1262570, R-483, CS-011 (rivoglitazone).

In one embodiment of the invention, the compound of the formula I isadministered in combination with Competact™, a fixed combination ofpioglitazone hydrochloride with metformin hydrochloride.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Tandemact™, a fixed combination ofpioglitazone with glimepride.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a fixed combination of pioglitazonehydrochloride with an angiotensin II agonist such as, for example,TAK-536.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR (peroxisome proliferatoractivated receptor) alpha agonist such as, for example, GW9578,GW-590735, K-111, LY-674, KRP-101, DRF-10945, LY-518674 or thosedescribed in WO2001040207, WO2002096894, WO2005097076.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a mixed PPAR (peroxisome proliferatoractivated receptor) alpha/gamma agonist such as, for example,naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847,CKD-501 (lobeglitazone sulfate) or as described in PCT/US 00/11833,PCT/US 00/11490, DE10142734.4 or in J. P. Berger et al., TRENDS inPharmacological Sciences 28(5), 244-251, 2005.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR (peroxisome proliferatoractivated receptor) delta agonist such as, for example, GW-501516 or asare described in WO2006059744, WO2006084176, WO2006029699,WO2007039172-WO2007039178.

In one embodiment, the compound of the formula I is administered incombination with metaglidasen or with MBX-2044 or other partial PPAR(peroxisome proliferator activated receptor) gamma agonists/antagonists.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a fibrate such as, for example,fenofibrate, clofibrate, bezafibrate.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an MTP inhibitor (microsomaltriglyceride transfer protein) such as, for example, implitapide,BMS-201038, R-103757, AS-1552133 or those described in WO2005085226,WO2005121091, WO2006010423.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a CETP inhibitor (cholesterol estertransfer protein) such as, for example, torcetrapib or JTT-705 or thosedescribed in WO2006002342, WO2006010422, WO2006012093, WO2006073973,WO2006072362, WO2006097169, WO2007041494.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a bile acid absorption inhibitor (see,for example, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897 orWO00/61568), such as, for example, HMR 1741 or those as described in DE10 2005 033099.1 and DE 10 2005 033100.9, WO2007009655-56.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a polymeric bile acid adsorber such as,for example, cholestyramine or colesevelam.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an LDL receptor inducer (Low DensityLipoprotein; see U.S. Pat. No. 6,342,512), such as, for example,HMR1171, HMR1586 or those as described in WO2005097738.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ABCA1 expression enhancer as aredescribed for example in WO2006072393.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with an RNAi therapeutic agent which isdirected against PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9).

In one embodiment, the compound of the formula I is administered incombination with Omacor® (omega-3 fatty acids; highly concentrated ethylesters of eicosapentaenoic acid and of docosahexaenoic acid).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ACAT inhibitor (acyl-CoA:cholesterolacyltransferase) such as, for example, avasimibe or SMP-797.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an antioxidant such as, for example,OPC-14117, probucol, tocopherol, ascorbic acid, β-carotene or selenium.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a vitamin such as, for example, vitaminB6 or vitamin B12.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein lipase modulator such as,for example, ibrolipim (NO-1886).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ATP citrate lyase inhibitor(adenosine triphosphate) such as, for example, SB-204990.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a squalene synthetase inhibitor suchas, for example, BMS-188494, TAK-475 or as described in WO2005077907,JP2007022943.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein(a) antagonist such as,for example, gemcabene (CI-1027).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an agonist of GPR109A (HM74A receptoragonist; NAR agonist (nicotinic acid receptor agonist)), such as, forexample, nicotinic acid or extended release niacin in conjunction withMK-0524A or those compounds described in WO2006045565, WO2006045564,WO2006069242, WO2006124490, WO2006113150, WO2007017261, WO2007017262,WO2007017265, WO2007015744, WO2007027532.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an agonist of GPR116 as are describedfor example in WO2006067531, WO2006067532.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipase inhibitor such as, forexample, orlistat or cetilistat (ATL-962).

In one embodiment of the invention, the compound of the formula I isadministered in combination with insulin.

In one embodiment, the compound of the formula I is administered incombination with a sulfonylurea such as, for example, tolbutamide,glibenclamide, glipizide, gliclazide or glimepiride.

In one embodiment, the compound of the formula I is administered incombination with a substance which enhances insulin secretion, such as,for example, KCP-265 (WO2003097064) or those described in WO2007026761.

In one embodiment, the compound of the formula I is administered incombination with agonists of the glucose-dependent insulinotropicreceptor (GDIR) such as, for example, APD-668.

In one embodiment, the compound of the formula I is administered incombination with a biguanide such as, for example, metformin.

In yet another embodiment, the compound of the formula I is administeredin combination with a meglitinide such as, for example, repaglinide,nateglinide or mitiglinide.

In a further embodiment, the compound of the formula I is administeredwith a combination of mitiglinide with a glitazone, e.g. pioglitazonehydrochloride.

In a further embodiment, the compound of the formula I is administeredwith a combination of mitiglinide with an alpha-glucosidase inhibitor.

In one embodiment, the compound of the formula I is administered incombination with a thiazolidinedione such as, for example, troglitazone,ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed inWO 97/41097 of Dr. Reddy's Research Foundation, in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment, the compound of the formula I is administered incombination with an α-glucosidase inhibitor such as, for example,miglitol or acarbose.

In one embodiment, the compound of the formula I is administered incombination with an active ingredient which acts on the ATP-dependentpotassium channel of the beta cells, such as, for example, tolbutamide,glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment, the compound of the formula I is administered incombination with more than one of the aforementioned compounds, e.g. incombination with a sulfonylurea and metformin, a sulfonylurea andacarbose, repaglinide and metformin, insulin and a sulfonylurea, insulinand metformin, insulin and troglitazone, insulin and lovastatin, etc.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of glycogen phosphorylase, such as, forexample, PSN-357 or FR-258900 or those as described in WO2003084922,WO2004007455, WO2005073229-31 or WO2005067932.

In one embodiment, the compound of the formula I is administered incombination with glucagon receptor antagonists such as, for example,A-770077 or NNC-25-2504 or as described in WO2004100875 or WO2005065680.

In one embodiment, the compound of the formula I is administered incombination with activators of glucokinase, such as, for example,R-1511, R-1440, LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50 orthose as are described for example in WO2004072031, WO2004072066,WO2005080360, WO2005044801, WO2006016194, WO2006058923, WO2006112549,WO2006125972, WO2007017549, WO2007017649, WO2007007910, WO2007007040-42,WO2007006760-61, WO2007006814, WO2007007886, WO2007028135, WO2007031739,WO2007041365, WO2007041366, WO2007037534, WO2007043638, WO2007053345,WO2007051846, WO2007051845, WO2007053765, WO2007051847.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of gluconeogenesis, such as, for example,FR-225654.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of fructose-1,6-bisphosphatase (FBPase),such as, for example, CS-917 (MB-06322) or MB-07803 or those describedin WO2006023515, WO2006104030, WO2007014619.

In one embodiment, the compound of the formula I is administered incombination with modulators of glucose transporter 4 (GLUT4), such as,for example, KST-48 (D.-O. Lee et al.: Arzneim.-Forsch. Drug Res. 54(12), 835 (2004)).

In one embodiment, the compound of the formula I is administered incombination with TNF agonists (tumor necrosis factor).

In one embodiment, the compound of the formula I is administered incombination with CRF agonists (corticotropin-releasing factor).

In one embodiment, the compound of the formula I is administered incombination with 5HT agonists (serotonin reuptake).

In one embodiment, the compound of the formula I is administered incombination with TR-β agonists (thyroid receptor).

In one embodiment, the compound of the formula I is administered incombination with inhibitors of glutamine-fructose-6-phosphateamidotransferase (GFAT), as are described for example in WO2004101528.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of dipeptidylpeptidase IV (DPP-IV), such as,for example, vildagliptin (LAF-237), sitagliptin (MK-0431), sitagliptinphosphate, saxagliptin (BMS-477118), GSK-823093, PSN-9301, SYR-322,SYR-619, TA-6666, TS-021, GRC-8200, GW-825964X, KRP-104, DP-893,ABT-341, ABT-279 or another salt thereof or those compounds as aredescribed in WO2003074500, WO2003106456, WO2004037169, WO200450658,WO2005058901, WO2005012312, WO2005/012308, WO2006039325, WO2006058064,PCT/EP2005/007821, PCT/EP2005/008005, PCT/EP2005/008002,PCT/EP2005/008004, PCT/EP2005/008283, DE 10 2005 012874.2, DE 10 2005012873.4, JP2006160733, WO2006071752, WO2006065826, WO2006078676,WO2006073167, WO2006068163, WO2006090915, WO2006104356, WO2006127530,WO2006111261, WO2007015767, WO2007024993, WO2007029086.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Janumet™, a fixed combination ofsitagliptin phosphate with metformin hydrochloride.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of 11-beta-hydroxysteroid dehydrogenase 1(11β-HSD1), such as, for example, BVT-2733, JNJ-25918646, INCB-13739 orthose as are described for example in WO200190090-94, WO200343999,WO2004112782, WO200344000, WO200344009, WO2004112779, WO2004113310,WO2004103980, WO2004112784, WO 2003065983, WO2003104207, WO2003104208,WO2004106294, WO2004011410, WO2004033427, WO2004041264, WO2004037251,WO2004056744, WO2004058730, WO2004065351, WO2004089367, WO2004089380,WO2004089470-71, WO2004089896, WO2005016877, WO2005097759, WO2006010546,WO2006012227, WO2006012173, WO2006017542, WO2006034804, WO2006040329,WO2006051662, WO2006048750, WO2006049952, WO2006048331, WO2006050908,WO2006024627, WO2006040329, WO2006066109, WO2006074244, WO2006078006,WO2006106423, WO2006132436, WO2006134481, WO2006134467, WO2006135795,WO2006136502, WO2006138695, WO2006133926, WO2007003521, WO2007007688,US2007066584, WO2007047625, WO2007051811, WO2007051810.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of protein tyrosine phosphatase 1B (PTP1B),as are described for example in WO200119830-31, WO200117516,WO2004506446, WO2005012295, WO2005116003, PCT/EP2005/005311,PCT/EP2005/005321, PCT/EP2005/007151, DE 10 2004 060542.4, WO2007009911,WO2007028145.

In one embodiment, the compound of the formula I is administered incombination with modulators of the sodium-dependent glucose transporter1 or 2 (SGLT1, SGLT2), such as, for example, KGA-2727, T-1095, SGL-0010,AVE 2268, SAR 7226 and sergliflozin or as are described for example inWO2004007517, WO200452903, WO200452902, PCT/EP2005/005959, WO2005085237,JP2004359630, WO2005121161, WO2006018150, WO2006035796, WO2006062224,WO2006058597, WO2006073197, WO2006080577, WO2006087997, WO2006108842,WO2007000445, WO2007014895 or by A. L. Handlon in Expert Opin. Ther.Patents (2005) 15(11), 1531-1540.

In one embodiment, the compound of the formula I is administered incombination with modulators of GPR119b as are described for example inWO2004041274.

In one embodiment, the compound of the formula I is administered incombination with modulators of GPR119 as are described for example inWO2005061489 (PSN-632408), WO2004065380, WO2007003960-62 andWO2007003964.

In a further embodiment, the compound of the formula I is administeredin combination with modulators of GPR120.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of hormone-sensitive lipase (HSL) and/orphospholipases as described for example in WO2005073199, WO2006074957,WO2006087309, WO2006111321, WO2007042178.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of acetyl-CoA carboxylase (ACC) such as, forexample, those described in WO199946262, WO200372197, WO2003072197,WO2005044814, WO2005108370, JP2006131559, WO2007011809, WO2007011811,WO2007013691.

In a further embodiment, the compound of the formula I is administeredin combination with modulators of xanthine oxidoreductase (XOR).

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of phosphoenolpyruvate carboxykinase(PEPCK), such as, for example, those as described in WO2004074288.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of glycogen synthase kinase-3 beta (GSK-3beta), as described for example in US2005222220, WO2005085230,PCT/EP2005/005346, WO2003078403, WO2004022544, WO2003106410,WO2005058908, US2005038023, WO2005009997, US2005026984, WO2005000836,WO2004106343, EP1460075, WO2004014910, WO2003076442, WO2005087727 orWO2004046117.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of the serum/glucocorticoid regulatedkinase (SGK) as described for example in WO2006072354.

In one embodiment, the compound of the formula I is administered incombination with an agonist of the RUP3 receptor as described forexample in WO2007035355.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of protein kinase C beta (PKC beta) suchas, for example, ruboxistaurin.

In another embodiment, the compound of the formula I is administered incombination with an activator of the gene which codes for the ataxiatelangiectasia mutated (ATM) protein kinase, such, for example,chloroquine.

In one embodiment, the compound of the formula I is administered incombination with an endothelin A receptor antagonist such as, forexample, avosentan (SPP-301).

In one embodiment, the compound of the formula I is administered incombination with inhibitors of “I-kappaB kinase” (IKK inhibitors), asare described for example in WO2001000610, WO2001030774, WO2004022553,WO2005097129.

In one embodiment, the compound of the formula I is administered incombination with modulators of the glucocorticoid receptor (GR), likethose described for example in WO2005090336, WO2006071609, WO2006135826.

In a further embodiment, the compound of the formula I is administeredin combination with CART modulators (see “Cocaine-amphetamine-regulatedtranscript influences energy metabolism, anxiety and gastric emptying inmice” Asakawa, A. et al.: Hormone and Metabolic Research (2001), 33(9),554-558);

NPY antagonists (neuropeptide Y) such as, for example,naphthalene-1-sulfonic acid{4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}amidehydrochloride (CGP 71683A);NPY-5 receptor antagonists such as L-152804 or like those described, forexample, in WO2006001318;NPY-4 receptor antagonists like those described for example inWO2007038942;NPY-2 receptor antagonists like those described for example inWO2007038943;peptide YY 3-36 (PYY3-36) or analogous compounds, such as, for example,CJC-1682 (PYY3-36 conjugated with human serum albumin via Cys34),CJC-1643 (derivative of PYY3-36 which conjugates in vivo to serumalbumin) or those as are described in WO2005080424, WO2006095166;derivatives of the peptide obestatin as described in WO2006096847;CB1R (cannabinoid receptor 1) antagonists (such as, for example,rimonabant, SR147778, SLV-319, AVE-1625, MK-0364 or salts thereof orthose compounds as are described for example in EP 0656354, WO 00/15609,WO 02/076949, WO2005080345, WO2005080328, WO2005080343, WO2005075450,WO2005080357, WO200170700, WO2003026647-48, WO200302776, WO2003040107,WO2003007887, WO2003027069, U.S. Pat. No. 6,509,367, WO200132663,WO2003086288, WO2003087037, WO2004048317, WO2004058145, WO2003084930,WO2003084943, WO2004058744, WO2004013120, WO2004029204, WO2004035566,WO2004058249, WO2004058255, WO2004058727, WO2004069838, US20040214837,US20040214855, US20040214856, WO2004096209, WO2004096763, WO2004096794,WO2005000809, WO2004099157, US20040266845, WO2004110453, WO2004108728,WO2004000817, WO2005000820, US20050009870, WO200500974, WO2004111033-34,WO200411038-39, WO2005016286, WO2005007111, WO2005007628, US20050054679,WO2005027837, WO2005028456, WO2005063761-62, WO2005061509, WO2005077897,WO2006047516, WO2006060461, WO2006067428, WO2006067443, WO2006087480,WO2006087476, WO2006100208, WO2006106054, WO2006111849, WO2006113704,WO2007009705, WO2007017124, WO2007017126, WO2007018459, WO2007016460,WO2007020502, WO2007026215, WO2007028849, WO2007031720, WO2007031721,WO2007036945, WO2007038045, WO2007039740, US20070015810, WO2007046548,WO2007047737);cannabinoid receptor 1/cannabinoid receptor 2 (CB1/CB2)-modulatingcompounds like those described for example in WO2007001939,WO2007044215, WO2007047737;MC4 agonists (melanocortin-4); e.g.1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]amide;(WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764,CHIR-785, PT-141 or those that are described in WO2005060985,WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720,US20050124652, WO2005051391, WO2004112793, WOUS20050222014,US20050176728, US20050164914, US20050124636, US20050130988,US20040167201, WO2004005324, WO2004037797, WO2005042516, WO2005040109,WO2005030797, US20040224901, WO200501921, WO200509184, WO2005000339,EP1460069, WO2005047253, WO2005047251, WO2005118573, EP1538159,WO2004072076, WO2004072077, WO2006021655-57, WO2007009894, WO2007015162,WO2007041061, WO2007041052; orexin receptor antagonists (e.g.1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride(SB-334867-A) or those as are described for example in WO200196302,WO200185693, WO2004085403, WO2005075458, WO2006067224); histamine H3receptor agonists (e.g.3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208) or those as are described in WO200064884,WO2005082893, WO2006107661, WO2007003804, WO2007016496, WO2007020213);histamine H1/histamine H3 modulators such as, for example, betahistineor its dihydrochloride;CRF antagonists (e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585));CRF BP antagonists (e.g. urocortin);urocortin agonists;agonists of the beta-3 adrenoceptor (such as, for example,1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanolhydrochloride (WO 01/83451) or solabegron (GW-427353) or N-5984(KRP-204) or those described in JP2006111553, WO2002038543,WO2007048840-843;MSH (melanocyte-stimulating hormone) agonists;MCH (melanin-concentrating hormone) receptor antagonists (such as, forexample, NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71,GW-803430 or compounds such as are described in WO2005085200,WO2005019240, WO2004011438, WO2004012648, WO2003015769, WO2004072025,WO2005070898, WO2005070925, WO2004039780, WO2004092181, WO2003033476,WO2002006245, WO2002089729, WO2002002744, WO2003004027, FR2868780,WO2006010446, WO2006038680, WO2006044293, WO2006044174, JP2006176443,WO2006018280, WO2006018279, WO2006118320, WO2006130075, WO2007018248,WO2007012661, WO2007029847, WO2007024004, WO2007039462, WO2007042660,WO2007042668, WO2007042669, US2007093508, US2007093509, WO2007048802,JP2007091649);CCK-A agonists (such as, for example,{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid (WO 99/15525) or SR-146131 (WO 0244150) or SSR-125180) or thosedescribed in WO2005116034;serotonin reuptake inhibitors (e.g. dexfenfluramine);mixed serotonin/dopamine reuptake inhibitors (e.g. bupropion) or fixedcombinations of bupropion with naltrexone;mixed serotoninergic and noradrenergic compounds (e.g. WO 00/71549);5-HT receptor agonists, e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalicacid salt (WO 01/09111);mixed dopamine/norepinephrine/acetylcholine reuptake inhibitors (e.g.tesofensine);5-HT2C receptor agonists (such as, for example, lorcaserinehydrochloride (APD-356) or BVT-933 or those as are described inWO200077010, WO200077001-02, WO2005019180, WO2003064423, WO200242304,WO2005035533, WO2005082859, WO2006077025, WO2006103511);5-HT6 receptor modulators such as, for example, E-6837 or BVT-74316 orthose described for example in WO2005058858, WO2007054257;bombesin receptor agonists (BRS-3 agonists);galanin receptor antagonists;growth hormone (e.g. human growth hormone or AOD-9604);growth hormone-releasing compounds tert-butyl(6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate(WO 01/85695));growth hormone secretagogue receptor antagonists (ghrelin antagonists)such as, for example, A-778193 or those as are described inWO2005030734;TRH agonists (thyrotrophin-releasing hormone, see, for example, EP 0 462884);uncoupling protein 2 or 3 modulators;leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.;Rozhayskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as apotential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881);DA agonists (dopamine agonists; bromocriptine, doprexin);lipase/amylase inhibitors (e.g. WO 00/40569);inhibitors of diacylglycerol O-acyltransferases (DGATs) as described forexample in BAY-74-4113 or as described for example in US2004/0224997,WO2004094618, WO200058491, WO2005044250, WO2005072740, JP2005206492,WO2005013907, WO2006004200, WO2006019020, WO2006064189, WO2006082952,WO2006120125, WO2006113919, WO2006134317, WO2007016538;inhibitors of fatty acid synthase (FAS) such as, for example, C75 orthose as described in WO2004005277;inhibitors of stearoyl-CoA delta9 desaturase (SCD1) like those describedfor example in WO2007009236, WO2007044085, WO2007046867, WO2007046868,WO20070501124;oxyntomodulin;oleoyl-estrone;or agonists or partial agonists of thyroid hormone receptor agonistssuch as, for example: KB-2115 or such as those described in WO20058279,WO200172692, WO200194293, WO2003084915, WO2004018421, WO2005092316,WO2007003419, WO2007009913, WO2007039125.

In one embodiment, the further active ingredient is vareniclinetartrate, a partial agonist of the alpha 4-beta 2 nicotinicacetylcholine receptor.

In one embodiment, the further active ingredient is trodusquemine

In one embodiment, the further active ingredient is a modulator of theenzyme SIRT1.

In one embodiment of the invention, the further active ingredient isleptin; see, for example, “Perspectives in the therapeutic use ofleptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, ExpertOpinion on Pharmacotherapy (2001), 2(10), 1615-1622.

In one embodiment, the further active ingredient is dexamphetamine oramphetamine.

In one embodiment, the further active ingredient is fenfluramine ordexfenfluramine.

In another embodiment, the further active ingredient is sibutramine.

In one embodiment, the further active ingredient is mazindole orphentermine.

In one embodiment, the further active ingredient is adiphenylazetidinone derivative as described for example in U.S. Pat. No.6,992,067 or U.S. Pat. No. 7,205,290.

In one embodiment, the compound of the formula I is administered incombination with bulking agents, preferably insoluble bulking agents(see, for example, Carob/CAROMAX® (Zunft H J; et al., Carob pulppreparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY(2001 September-October), 18(5), 230-6). Caromax is a carob-containingproduct from Nutrinova, Nutrition Specialties & Food Ingredients GmbH,Industriepark Hochst, 65926 Frankfurt/Main). Combination with CAROMAX®is possible in one preparation or by separate administration ofcompounds of the formula I and CAROMAX®. CAROMAX® can in this connectionalso be administered in the form of food products such as, for example,in bakery products or muesli bars.

It will be appreciated that every suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances isregarded as falling within the protection conferred by the presentinvention.

The examples detailed below serve to illustrate the invention without,however, restricting it.

TABLE 1 I

Link- Ex. R1 R2 R3 R4 R5 R6 m R7 R8 X age  1 Br H i-Pr H H — 0 H H—(CH₂)₂— 4  2 F H F H Cl — 0 H H —(CH₂)₂— 4  3 Cl Cl H Cl Cl — 0 H H—(CH₂)₂— 4  4 Cl H CF₃ H H — 0 H H —(CH₂)₂— 4  5 Br H CF₃ H H — 0 H H—(CH₂)₂— 4  6 Cl H F H H — 0 H H —(CH₂)₂— 4  7 Cl H Cl H H — 0 H H—(CH₂)₂— 4  8 H H CO₂Me H Me — 0 H H —(CH₂)₂— 4  9 CF₃ H i-Pr H H — 0 HH —(CH₂)₂— 4 10 CF₃ H CF₃ H H — 0 H H —(CH₂)₂— 4 11 Br H H CF₃ H — 0 H H—(CH₂)₂— 4 12 CF₃ H Br H H — 0 H H —(CH₂)₂— 4 13 H Cl Br H H — 0 H H—(CH₂)₂— 4 14 Cl H Br H H — 0 H H —(CH₂)₂— 4 15 Br H F H H — 0 H H—(CH₂)₂— 4 16 Br H Cl H H — 0 H H —(CH₂)₂— 4 17 Cl Cl H H H — 0 H H—(CH₂)₂— 4 18 CF₃ H Cl H H — 0 H H —(CH₂)₂— 4 19 H H Me H CO₂Me — 0 H H—(CH₂)₂— 4 20 Ph H i-Pr H H — 0 H H —(CH₂)₂— 4 21 H H i-Pr H Br — 0 H H—(CH₂)₂— 3 22 Cl H CF₃ H H — 0 H H —(CH₂)₂— 3 23 Cl H F H H — 0 H H—(CH₂)₂— 3 24 Cl Cl H Cl Cl — 0 H H —(CH₂)₂— 3 25 Cl H Cl H H — 0 H H—(CH₂)₂— 3 26 CF₃ H i-Pr H H H 0 H H —CH₂—CH(C≡C—CH₃)— 4 27 H Hcyclohexyl H H H 0 H H —(CH₂)₂— 4 28 F H Ph H H H 0 H H —(CH₂)₂— 4 29CF₃ H CF₃ H H H 0 H H —CH₂—CH(C≡C—CH₃)— 4 30 H Cl Br H H H 0 H H—CH₂—CH(C≡C—CH₃)— 4 31 H H i-Pr H H H 0 H H —(CH₂)₂— 4 32 Cl H t-Bu H HH 0 H H —(CH₂)₂— 4 33 H H 4-t-Bu-Ph H H H 0 H H —(CH₂)₂— 4 34 Br H t-BuH H H 0 H H —(CH₂)₂— 4 35 Cl H i-Pr H H H 0 H H —(CH₂)₂— 4

The activity of the compounds was tested as follows:

In-Vitro FLIPR Assay with Recombinant Cells which Express the GPCR GPR40

Function-testing assays were carried out by means of the FLIPR technique(“fluorescence imaging plate reader”, Molecular Devices Corp.). For thispurpose, agonist-induced alterations in the intracellular concentrationof Ca²⁺ in recombinant HEK293 cells which express the GPCR GPR40 weredetermined.

For the investigations, cells were seeded in 96-well microtiter plates(60 000 cells/well) and left to grow overnight. The medium was removedand the cells were incubated in buffer which contained the fluorescentdye Fluo-4. After this loading with dye, the cells were washed, testsubstance was added and alterations in the intracellular Ca²⁺concentration were measured in the FLIPR instrument. Results have beendepicted as percentage alteration relative to the control (0%: no testsubstance added; 100%: 10 μM reference agonist linoleic acid added) usedto calculate dose/activity plots and EC₅₀ values were determined

TABLE 2 Biological activity Ex. EC₅₀ [μM] 7 0.7 9 0.1 11 0.8 14 0.6 2116.8 24 60.1 26 0.2 29 0.1 30 0.1

It is evident from the table that the compounds of the formula Iactivate the GPR40 receptor and thus are very suitable for the treatmentof hyperglycemia and diabetes. The insulin secretion is increased by thecompounds of the formula I (see Itoh et al., Nature 2003, 422, 173-176).

Owing to the activation of the GPR40 receptor, the compounds of theformula I can also be used for the treatment or prevention of furtherdiseases.

The compounds of the present invention are particularly suitable for thetreatment and/or prevention of:

-   1. disorders of fatty acid metabolism and glucose utilization    disorders    -   disorders in which insulin resistance is involved-   2. Diabetes mellitus, especially type 2 diabetes, including the    prevention of the sequelae associated therewith.    -   Particular aspects in this connection are    -   hyperglycemia,    -   improvement in insulin resistance,    -   improvement in glucose tolerance,    -   protection of the pancreatic β cells    -   prevention of macro- and microvascular disorders-   3. Various other conditions which may be associated with the    metabolic syndrome or syndrome X, such as:    -   increased abdominal girth    -   dyslipidemia (e.g. hypertriglyceridemia and/or low HDL)    -   insulin resistance    -   hypercoagulability    -   hyperuricemia    -   microalbuminemia    -   thromboses, hypercoagulable and prothrombotic states (arterial        and venous)    -   high blood pressure    -   heart failure such as, for example (but not restricted thereto),        following myocardial infarction, hypertensive heart disease or        cardiomyopathy-   4. Memory impairments, intellectual deficits, CNS disorders such as    -   dementia in the elderly    -   Alzheimer's disease    -   treatment of diminished attention or vigilance    -   schizophrenia

The compounds of the formula I can be prepared for example by convertingsuitable starting materials of the formula II

with oxalyl chloride into the oxamoyl chlorides of the formula III

in suitable solvents such as, for example, ethyl acetate oracetonitrile. The compounds of the formula III prepared in this way arereacted with aminophenyl-substituted carboxylic acids of the formula IV

in suitable solvents such as, for example, acetonitrile,1,2-dichloroethane or dichloromethane at suitable temperatures,preferably at the boiling point, to give compounds of the formula I.

The general preparation of the examples is described in detail below:

Experimental Section General Experimental Procedure: Preparation of theOxamoyl Chloride:

500 mg of an aniline are dissolved in 5 ml of ethyl acetate and addeddropwise over the course of one hour to a solution of 500 mg of oxalylchloride in 5 ml of ethyl acetate. The reaction solution is stirred atroom temperature for 2 hours and then concentrated.

Preparation of the Oxamides of the Formula I:

The aminophenyl-substituted carboxylic acid is added in portions to asolution of the oxamoyl chloride in 10 ml of acetonitrile and stirred at100° C. for 16 hours. The resulting precipitate is filtered off withsuction and, if necessary, purified by flash chromatography (SiO₂,dichlormethane-isopropanol).

The compounds were analyzed by LC/MS. The appropriate molecular peak(M+H)+ was detectable by LC/MS for all examples.

1-18. (canceled)
 19. A method for lowering blood glucose, for treatingdiabetes, a CNS disorder, schizophrenia, or Alzheimer's disease, or forincreasing insulin secretion, in a patient in need thereof, comprisingadministering to the patient a pharmaceutically effective amount of thecompound according to formula I

wherein: R3 is H, F, Cl, Br, CN, CF₃, OH, OCF₃, OCHF₂, SCH₃, SCF₃,phenyl, Ophenyl, COOH, COO—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, O—(C₁-C₆) alkyl, OBn,SO₂—(C₁-C₄)-alkyl, SO₃H SO₂NR9R10, NR9R10 or SO₂—N-piperidinyl, whereinthe alkyl and phenyl are optionally substituted one or more times byR12; R1 and R5 are, independently, H, F, Cl, Br, CN, CF₃, SCH₃, SCF₃,phenyl, O-phenyl, COOH, COO—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, SO₂—(C₁-C₄)-alkyl, SO₃H, SO₂NR9R10, NR9R10 orSO₂—N-piperidinyl, wherein the alkyl and phenyl are optionallysubstituted one or more times by R12; R2 and R4 are, independently, H,F, Cl, Br, CN, CF₃, OCF₃, OCHF₂, SCH₃, SCF₃, phenyl, O-phenyl, COOH,COO—(C₁-C₆)-alkyl, CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl,O-Bn, SO₂—(C₁-C₄)-alkyl, SO₃H, SO₂NR9R10, NR9R10 or SO₂—N-piperidinyl,wherein the alkyl and phenyl are optionally substituted one or moretimes by R12; R7 and R8 are, independently, H or (C₁-C₆)-alkyl; X is(C₂-C₃)-alkylene optionally substituted one or more times by R11; m is0, 1, 2, 3 or 4; R6 is OH, F, Cl, Br, CN, OCH₃, OCF₃, CH₃, CF₃,(C₁-C₆)-alkyl or O—(C₁-C₆)-alkyl, wherein the alkyl is optionallysubstituted one or more times by OH, F, Cl, Br or CN; R9 and R10 are,independently, H, (C₁-C₆)-alkyl or phenyl, wherein the alkyl isoptionally substituted one or more times by F, Cl or Br, and the phenylis optionally substituted one or more times by R6; R11 is F, Cl, Br, CN,OH, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl orNR9R10; and R12 is F, Cl, Br, CN, OH, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,(C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, NR9R10, COOH, COO—(C₁-C₄)-alkyl, SCH₃,SCF₃, SO₂—(C₁-C₄)-alkyl, SO₃H or SO₂NR9R10; or a pharmaceuticallyacceptable salt thereof.
 20. (canceled)
 21. The method according toclaim 19, wherein R3 is H, F, Cl, Br, CF₃, OCF₃, COOH,COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₈)-Cycloalkyl, phenyl, orO-phenyl, wherein the alkyl and phenyl are optionally substituted one ormore times by R12; R1 and R5 are, independently, H, F, Cl, Br, CF₃,COOH, COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, phenyl, or Ophenyl, wherein thealkyl and phenyl are optionally substituted one or more times by R12; R2and R4 are, independently, H, F, Cl, Br, CF₃, COOH, COO—(C₁-C₆)-alkyl,or (C₁-C₆)-alkyl; R7 and R8 are H; m is 0; and R12 is F, Cl, Br, CN, OH,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,NR9R10, COOH, or COO—(C₁-C₄)-alkyl; or a pharmaceutically acceptablesalt thereof.
 22. The method according to claim 19, wherein R3 is H, F,Cl, Br, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl,(C₃-C₈)-cycloalkyl, or phenyl; R1 and R5 are, independently, H, F, Cl,Br, CF₃, COOH, COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, or phenyl; R2 and R4are, independently, H, F, Cl, Br, CF₃, COOH, COO—(C₁-C₆)-alkyl, or(C₁-C₆)-alkyl; R7 and R8 are H; m is 0; and R11 is (C₂-C₆)-alkynyl; or apharmaceutically acceptable salt thereof.
 23. The method according toclaim 19, wherein R3 is H, F, Cl, Br, CF₃, OCF₃, COOH,COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, or phenyl; R1 andR5 are, independently, H, F, Cl, Br, CF₃, COOH, COO—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, or phenyl; R2 and R4 are, independently, H, F, Cl, Br,CF₃, COOH, COO—(C₁-C₆)-alkyl, or (C₁-C₆)-alkyl; R7 and R8 are H; X is(C₂-C₃)-alkylene, where X is linked at position 4 to the ring; and m is0; or a pharmaceutically acceptable salt thereof.
 24. The methodaccording to claim 19, wherein R3 is H, F, Cl, Br, CN, CF₃, OH, OCF₃,OCHF₂, SCH₃, SCF₃, phenyl, O-phenyl, COOH, COO—(C₁-C₆)-alkyl,CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl, O-Bn,SO₂—(C₁-C₄)-alkyl, SO₃H, SO₂NR9R10, NR9R10 or SO₂—N-piperidinyl, whereinthe alkyl and phenyl are optionally substituted one or more times byR12; or a pharmaceutically acceptable salt thereof.
 25. The methodaccording to claim 19, wherein R3 is H, F, Cl, Br, CF₃, OCF₃, COOH,COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, phenyl, or O-phenyl, wherein the alkyland phenyl are optionally substituted one or more times by R12; R1 andR5 are, independently, H, F, Cl, Br, CF₃, COOH, COO—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, phenyl, or O-phenyl, wherein the alkyl and phenyl areoptionally substituted one or more times by R12; R2 and R4 are,independently, H, F, Cl, Br, CF₃, COOH, COO—(C₁-C₆)-alkyl, or(C₁-C₆)-alkyl; R7 and R8 are H; m is 0; and R12 is F, Cl, Br, CN, OH,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,NR9R10, COOH, or COO—(C₁-C₄)-alkyl; or a pharmaceutically acceptablesalt thereof.
 26. The method according to claim 19, wherein R3 is H, F,Cl, Br, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, or phenyl; R1and R5 are, independently, H, F, Cl, Br, CF₃, COOH, COO—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, or phenyl; R2 and R4 are, independently, H, F, Cl, Br,CF₃, COOH, COO—(C₁-C₆)-alkyl, or (C₁-C₆)-alkyl; R7 and R8 are H; X is(C₂-C₃)-alkylene; and m is 0; or a pharmaceutically acceptable saltthereof.
 27. The method according to claim 19, wherein R3 is H, F, Cl,Br, CF₃, OCF₃, COOH, COO—(C₁-C₆)-alkyl, or (C₁-C₆)-alkyl; R1 and R5 are,independently, H, F, Cl, Br, CF₃, COOH, COO—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, or phenyl; R2 and R4 are, independently, H, F, Cl, Br,CF₃, COOH, COO—(C₁-C₆)-alkyl, or (C₁-C₆)-alkyl; R7 and R8 are H; X is(C₂-C₃)-alkylene, where X is linked at position 4 to the ring; and m is0; or a pharmaceutically acceptable salt thereof.